(xe2x88x92)cis-3-Hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine (II) is a central building block in the synthesis of flavopiridol (I) (HMR 1275 or L86-8275), the first potent inhibitor of the cyclin-dependent protein kinase (see, for example, Sedlacek, Hans Harald; Czech, Joerg; Naik, Ramachandra; Kaur, Gurmeet; Worland, Peter; Losiewicz, Michael; Parker, Bernard; Carlson, Bradley; Smith, Adaline; et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. (1996), 9(6), 1143-1168 or Czech, Joerg; Hoffmann, Dieter; Naik, Ramachandra; Sedlacek, Hans-Harald. Antitumoral activity of flavone L 86-8275. Int. J. Oncol. (1995), 6(1), 31-36). 
The process for the preparation of (II) previously described in EP-B 0 241 003 and EP-B 0 366 061 is time-consuming and includes reactions (hydroboration, Swern oxidation, sodium borohydride reduction) which are difficult to handle on the industrial scale. Surprisingly, we have now found a significantly simpler preparation process, which is illustrated in Scheme 1. 
The process for the preparation of (xe2x88x92)cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine (II) 
comprises
a1) converting 1-methylpiperidin-4-one (III) 
xe2x80x83into the hydrobromide according to known processes, or
a2) converting 1-methylpiperidin-4-one (III) directly into the hydrobromide, prior to the subsequent bromination, by introduction of 1-methylpiperidin-4-one into an HBr/glacial acetic acid solution, and
b) reacting 1-methylpiperidin-4-one hydrobromide in a suitable solvent, acetic acid, in the temperature range from 0xc2x0 C.-30xc2x0 C. with bromine to give 3(R,S)-bromo-1-methyl-4-oxopiperidine hydrobromide (IV) 
c) reacting this intermediate (IV) directly by addition of 0.8-1 equivalent of 1,3,5-trimethoxybenzene (V) 
xe2x80x83to the reaction solution at 0-30xc2x0 C. to give 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) 
xe2x80x83and, if appropriate, additionally adding acetic anhydride to remove any water of reaction formed
d1) first isolating the compound (VI) as a solid by stirring the reaction solution into a suitable organic solvent, methyl tert-butyl ether, dichloromethane etc., and subsequently reacting the resulting product with water and by stirring at 50xc2x0-100xc2x0 C., preferably at 60xc2x0-80xc2x0 C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) 
xe2x80x83or
d2) treating the reaction mixture containing the compound (VI) directly with water and reacting by stirring at 50xc2x0-100xc2x0 C., preferably at 60xc2x0-80xc2x0 C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII), and
d3) cooling the reaction mixtures obtained according to d1) or d2), if appropriate diluting further with water and adjusting to pH greater than 12 at 0xc2x0-30xc2x0 C. by addition of aqueous alkali, preferably sodium hydroxide, 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) precipitating, filtering off the resulting crude product with suction and if appropriate, for purification, taking it up again in aqueous hydrochloric acid, filtering and optionally extracting with a water-immiscible solvent, e.g. ethyl acetate, and then adjusting the aqueous phase to pH greater than 12 by addition of aqueous alkali, preferably sodium hydroxide, 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) precipitating, extracting the precipitated product, if appropriate for further purification, with one or more suitable organic solvents, acetone, isopropanol, diisopropyl ether or alternatively mixtures of these solvents, and
e1) catalytically hydrogenating the resulting product (VII) in a suitable solvent, e.g. methanol, isopropanol, water or mixtures of these solvents using a suitable catalyst, e.g. palladium/carbon, rhodium/carbon etc., to give the racemic 3,4-cis alcohol (VIII) 
xe2x80x83where the 3,4-trans alcohol, which possibly results in small amounts during the reduction, can be removed by crystallization from suitable solvents, acetone, or
e2) for the hydrogenation, employing easily accessible esters (IXa) or carbonates (IXb) of the compound (VII) 
xe2x80x83in which R is (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl or (C6-C14)-aryl and in the formula (IXa) is further carboxy-(C2-C6)-alkyl;
compounds (Xa) and (Xb) being obtained, from which the compound (VIII) can be liberated by known procedures,
f1) obtaining the enantiomerically pure cis alcohol (II) from the compound (VIII) by a known process by resolution using suitable chiral auxiliary reagents such as, for example, ketopinic acid, or
f2) carrying out the resolution using the compounds (Xa) or (Xb) 
xe2x80x83where R is (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl or (C6-C14)-aryl and in the formula (Xa) is further carboxy-(C2-C6)-alkyl,
and then converting these into the compound (II) by known processes,
it also being possible to exchange the sequence of the reaction steps e) and f, i.e. also to carry out the resolution as early as at the stage of the allyl alcohol (VII) or of the compounds (IXa) and (IXb) obtained therefrom.
In analogy to a process described in the literature (Trost et al., JACS 1994, 116, 10320), the esters (IXa) or carbonates (IXb) are suitable for the deracemization to give the enantiomerically pure esters. After hydrogenation and ester cleavage, (xe2x88x92)cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine (II) is then obtained.
3(R,S)-Bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) and 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) are valuable intermediates in the preparation of (xe2x88x92)cis-3-hydroxy-1-methyl-4(2,4,6-trimethoxyphenyl)piperidine (II).